HIV-1 In MT-4 Cells Research Articles

Synthesis, anti-HIV and cytotoxicity evaluation of chiral 2,5-disubstituted 1,3,4-thiadiazole derivatives bearing the sulfonamide scaffold

Abstract In the present study, chiral 2-(4-substiuted phenyl)amino-5-[1-(4-substituted benzenesulphonamido)alkyl]-1,3,4-thiazdiazoles 5a–x were synthesized from enantiopure l-amino acids in a multistep sequence. The starting acids were reacted with arylsulphonyl chlorides to produce N-arylsulfonyl amino acids 1a–h, followed by esterification to obtain the corresponding esters 2a–h. Treatment of esters with hydrazine hydrate afforded the corresponding hydrazides 3a–h. The coupling of hydrazides with aryl isothiocyanates followed by cyclization gave the target thiadiazoles 5a–x in good yields. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells using MTT assay. Compounds 5s, 5v and 5w showed IC50 values of > 1.58, >1.98 and > 2.04 μm with SI > 1, respectively, indicating that these compounds were cytotoxic at concentrations values of 1.58, 1.98 and 2.04 μm, respectively.

A New Approach to Developing Long-Acting Injectable Formulations of Anti-HIV Drugs: Poly(Ethylene Phosphoric Acid) Block Copolymers Increase the Efficiency of Tenofovir against HIV-1 in MT-4 Cells.

Despite the world’s combined efforts, human immunodeficiency virus (HIV), the causative agent of AIDS, remains one of the world’s most serious public health challenges. High genetic variability of HIV complicates the development of anti-HIV vaccine, and there is an actual clinical need for increasing the efficiency of anti-HIV drugs in terms of targeted delivery and controlled release. Tenofovir (TFV), a nucleotide-analog reverse transcriptase inhibitor, has gained wide acceptance as a drug for pre-exposure prophylaxis or treatment of HIV infection. In our study, we explored the potential of tenofovir disoproxil (TFD) adducts with block copolymers of poly(ethylene glycol) monomethyl ether and poly(ethylene phosphoric acid) (mPEG-b-PEPA) as candidates for developing a long-acting/controlled-release formulation of TFV. Two types of mPEG-b-PEPA with numbers of ethylene phosphoric acid (EPA) fragments of 13 and 49 were synthesized by catalytic ring-opening polymerization, and used for preparing four types of adducts with TFD. Antiviral activity of [mPEG-b-PEPA]TFD or tenofovir disoproxil fumarate (TDF) was evaluated using the model of experimental HIV infection in vitro (MT-4/HIV-1IIIB). Judging by the values of the selectivity index (SI), TFD exhibited an up to 14-fold higher anti-HIV activity in the form of mPEG-b-PEPA adducts, thus demonstrating significant promise for further development of long-acting/controlled-release injectable TFV formulations.

Synthesis, In Vitro Anti-HIV Activity, Cytotoxicity, and Computational Studies of Some New Steroids and Their Pyrazoline and Oxime Analogues

There is an urgent need for the design and development of new and safer drugs for the treatment of HIV infection, active against the currently resistant viral strains by development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of pregnenolone analogues, 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones, were synthesized. Further, treatment of 3-((4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-ones with thiosemicarbazide in ethanolic KOH or hydrazine hydrate in HOAc gave 5-(4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline, respectively. Analogously, treatment of 3-((4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one with hydroxylamine afforded the Z/E isomers of 3-(4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one oxime. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 3-(thiophene-2-yl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline were the most active in inhibiting HIV-1 and HIV-2 with IC50 = 60.5 μM (SI > 2, against HIV-2 and SI 0.29 μM (SI < I), respectively, suggesting to be new leads in the development of antiviral agents. QSAR of 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones and 5-(substituted phenyl)-3-(5-preg-5-3β-ol-17-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamides has been studied. The conformational analysis of 5-(4-trifluoromethylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamide and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline as well as the molecular docking study of the latter compound have been investigated.

A Click Synthesis, Molecular Docking, Cytotoxicity on Breast Cancer (MDA-MB 231) and Anti-HIV Activities of New 1,4-Disubstituted-1,2,3-Triazole Thymine Derivatives

A new series of 1,4-disubstituted-1,2,3-triazolethymine derivatives (VIa–e) were synthesized and characterized by spectroscopic studies. The in vitro cytotoxic activities of selected compounds against human cancer cell line (MDA-MB 231) were evaluated by MTT assay. 4-Azido-N-substituted-benzenesulfonamides (Vc–e) and 4,4'-(4,4'-((5-methyl-2,4-dioxopyrimidine-1,3(2H,4H)-diyl)bis(methylene))-bis(1H-1,2,3-triazole-4,1-diyl))-bis(N-(4-methyl pyrimidin-2-yl)benzenesulfonamide) (VIc) displayed a significant cytotoxic activity with IC50 values of 1.61, 1.41, 1.61 and 1.81 μM, respectively. Molecular docking study of 4‑azido-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (Vd) and 4,4'-(4,4'-((5-methyl-2,4-dioxopyrimidine-1,3(2H,4H)-diyl)bis(methylene))-bis(1H-1,2,3-triazole-4,1-diyl))-bis (N-(4-methyl pyrimidin-2-yl)benzenesulfonamide) (VIc) showed hydrogen bonding with the amino acid residues of the receptors 1X7R and 1A53, respectively. These derivatives are useful as starting points for further study of new anticancer drugs and to confirm the potential of triazole-sulfonamide analogues as lead compounds in anticancer drug discovery. In addition, 1,4-disubstituted-1,2,3-triazolethymine derivatives (VIa–e) were evaluated in vitro for antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells. The results showed that 1,4-disubstituted-1,2,3-triazolethymine derivatives (VIc–e) possess a potent activity against HIV-1 replication with IC50 values of 11.42, ≥15.25,and 14.36 μM, SI > 4, ≤6, >9, respectively.

Microwave-assisted synthesis, molecular docking and anti-HIV activities of some drug-like quinolone derivatives

In targeted therapy of breast cancer, human epidermal growth factor receptor 2 HER2 (PDB ID: 3PP0) is being considered as a promising route to design novel anti-breast cancer drugs. In this work, we report two of novel N-substituted pyrrolidine at C-8 position of quinolone derivatives 18 and 19, their synthesis under microwave technique, spectral methods, molecular docking study and anti-HIV activities. Docking study exhibited hydrogen bonding, polar, and Van der Waals interactions with the active site residues of HER2 target. The binding energy and hydrogen bonding interactions show that synthesized compounds are being considered to have a potential activity against breast cancer. In addition, quinolone derivatives were evaluated in vitro for antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells. The results showed that quinolone derivatives 18 and 19 possess a potent activity against HIV-1 replication with IC50 values of ≥15.20 and 14.26 μM, SI ≤ 6 and >7, respectively.

Synthesis, anti-HIV activity, molecular modeling study and QSAR of new designed 2-(2-arylidenehydrazinyl)-4-arylthiazoles

Taking into consideration the eminence of 1,3-thiazoles in medicinal chemistry and in a view of procuring more pronounced biological contour, the synthesis of 2-(2-arylidenehydrazinyl)-4-arylthiazoles 6–43 was made possible by the cyclization reaction of thiosemicarbazones and α-bromoacetophenones. The thiosemicarbazones 5a-m were in turn synthesized from substituted benzaldehydes or acetophenones and thiosemicarbazide. Optimization of the reaction conditions was carried out in order to attain the target molecules in good yields. All the new compounds were evaluated in vitro for their antiviral activity against the replication of HIV-1 and HIV-2 in MT4 cells using a MTT assay. Screening results indicated that compounds 32–34 are the only compounds in the series inhibiting HIV-1 and HIV-2 replication in cell cultures with IC50 of >2.71, >2.19 and > 1.71 μM, respectively. The molecular docking of compounds 32 and 34 with some amino acids of human immunodeficiency virus reverse transcriptase (HIV RT) were also studied. The preliminary quantum structure-activity relationship (QSAR) among the newly synthesized congeners was obtained by two methods, Multiple Linear Regression (MRL) and Genetic Function Approximation (GFA).

Synthesis of new chiral 1,3,4-thiadiazole-based di- and tri-arylsulfonamide residues and evaluation of in vitro anti-HIV activity and cytotoxicity.

A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a-4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a-2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a-3f. Treatment of 2a-2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a-4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC50 = 9.5μM (SI = 6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of > 4.09μM and could be a promising antiproliferative agent.

Discovery of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs Targeting the Tolerant Region I of NNIBP.

Our previous studies led us to conclude that thiophene[3,2-d]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (J. Med. Chem. 2016, 59, 7991-8007; J. Med. Chem. 2017, 60, 4424-4443). In the present study, we designed and synthesized a series of thiophenepyrimidine derivatives with various substituents in the right wing region of the structure with the aim of developing new interactions with the tolerant region I of the binding pocket of the HIV-1 non-nucleoside reverse transcriptase (NNRTI), and we evaluated their activity against a panel of mutant HIV-1 strains. All the derivatives exhibited moderate to excellent potency against wild-type (WT) HIV-1 in MT-4 cells. Among them, sulfonamide compounds 9b and 9d were single-figure-nanomolar inhibitors with EC50 values of 9.2 and 7.1 nM, respectively. Indeed, 9a and 9d were effective against the whole viral panel except RES056. Notably, both compounds showed potent antiviral activity against K103N (EC50 = 0.032 and 0.070 μM) and E138K (EC50 = 0.035 and 0.045 μM, respectively). Furthermore, 9a and 9d exhibited high affinity for WT HIV-1 RT (IC50 = 1.041 and 1.138 μM, respectively) and acted as classical NNRT inhibitors (NNRTIs). These results are expected to be helpful in the design of thiophenepyrimidine-based NNRTIs with more potent activity against HIV strains with RT mutations.

Synthesis, crystal structure, anti-HIV, and antiproliferative activity of new pyrazolylthiazole derivatives

The development of new HIV-1 non-nucleoside reverse transcriptase inhibitors offers the possibility of generating novel structures of increased potency. Based on the bioisosteric principle, new series of N′-benzylidene-2-(5-(4-chlorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)thiazole-4-carbohydrazide schiff bases 5a–x containing 1,3-thiazole clubbed with 2-pyrazoline was synthesized and characterized by spectroscopic techniques. The structure of the synthesized compounds was unambiguously confirmed by single-crystal X-ray diffraction analysis of compound 5k. All the new analogs were evaluated in vitro for antiviral activity against the replication of HIV-1 and HIV-2 in MT4 cells using MTT assay. The results showed that only compounds 5n, and 5r possess potent activity against HIV-1 replication (IC50 = 0.50, 0.45 μM, SI = 3 and 5), respectively. None of the compounds are active against HIV-2. Furthermore, compounds 5a, 5i, 5n, and 5r were evaluated for their antiproliferative activity against two solid tumor-derived cell lines consisting MCF-7 (breast cancer) and Hep-G2 (human hepatocarcinoma).

Synthesis, X-ray structure, in vitro HIV and kinesin Eg5 inhibition activities of new arene ruthenium complexes of pyrimidine analogs

Three new ruthenium(II)-arene complexes of the general formula [{(η6-p-cymene)Ru(L)}2](Cl)2), where L are monastrol (L1), ethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-pyrimidine-5-carboxylate (L2) or its 4-bromophenyl analog (L3), have been synthesized and characterized by elemental analysis, 1H, 13C, and 2-D NMR spectroscopy. The X-ray diffraction study of complex 1 showed the presence of a dicationic diruthenium complex where two thioxopyrimidines act as tridentate μ,κN:κ2S ligand, bridging two Ru ions through the pyrimidine nitrogen and sulfur atoms. All new complexes were evaluated in vitro for their antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells using MTT assay. Additionally, complexes 1–3 were screened for their inhibitory activity against the ATPase enzyme and the motor-protein Kinesin Eg5. Complex 1 was found to inhibit microtubule-stimulated ATPase activity of kinesin of IC50 = 30 μM (monastrol, IC50 = 10 μM).

New chalcones and thiopyrimidine analogues derived from mefenamic acid: microwave-assisted synthesis, anti-HIV activity and cytotoxicity as antileukemic agents

AbstractThe development of new HIV non-nucleoside reverse transcriptase inhibitors offers the possibility of generating structures of increased potency. To this end, coupling of mefenamic acid (4) with 4-amino-acetophenone (6) in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP) reagents afforded 4-(acetyphenyl)-2-((2,3-dimethylphenyl)amino)benzamide (7). Analogously, treatment of mefenamyl chloride (5) prepared from4with6under microwave irradiation (MWI) afforded7. A new series of substituted chalconyl-incorporated amide derivatives of mefenamic acid8–13were synthesized from condensation of7with various substituted benzaldehydes via the Claisen–Schmidt reaction. Treatment of8and11with thiourea in a basic medium afforded the thiopyrimidine analogues14and15, respectively. The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds9and11showed cytotoxicity values of 2.17 and 2.06 μm, respectively, against mock-infected MT-4 cells (C type adult T leukemia cells), which considered to be promising antileukemic agents.

Synthesis, biological activity and modeling study of some thiopyrimidine derivatives and their platinum(II) and ruthenium(III) metal complexes

Abstract A new series of 6-amino-5-(aryldiazenyl)-N 1,N 3-dimethyl-2-thioxo-pyrimidin-4-one derivatives 17–27 and the N 1-methyl-azothiopyrimidine analog 28 were synthesized from the pyrimidine derivatives 4 and 5, respectively, via diazotization reaction, with various amines. The platinum(II) metal complexes [bis(4-amino-N 3-methyl-6-oxo-2-thioxo-pyrimidin-1-yl)]Pt(II) (29) and [(6-amino-5-(4-R-phenyl)diazenyl)-N 1 ,N 3-dimethyl-2-thioxo-pyrimidin-4-one)]Pt(II)Cl2 derivatives 30–33 were prepared from the treatment of 5 and the azo analogs 17 and 21–23 with PtCl2, respectively. Analogously, 5 and 17 were treated with RuCl3·3H2O to give the Ru(III) complexes 34 and 35, respectively. The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. The results revealed that 26 and 30 were the only compounds in the series inhibiting HIV replication in cell cultures with an IC50 value of &gt;2.07 and &gt;3.02 μg mL–1, respectively. The molecular modeling interactions of 26 with some amino acids of HIV reverse transcriptase were studied. In addition, the antibacterial activity of 17–35 and 31–33 against Staphylococcus aureus and Escherichia coli was evaluated.

Exploration of new 3α-pregnenolone ester analogues via Mitsunobu reaction, their anti-HIV activity and molecular modeling study

A new series of (5-pregnen-20-on-3α-yl)-substituted-benzoate analogues (10-13), (5-pregnene-20-on-3α-yl)-3-(substituted)acrylate derivatives (17-19) as well as the (17-(2-acetoxyacetyl)pregen-3α-yl)-3,4,5-trihydroxybenzoate (21) were synthesized from the β-pregenenolone scaffolds, by applying Mitsunobu reaction. All new compounds were characterized by 1 H, 13 C and 2D NMR spectroscopy. The inversion in configuration at C-3 during the formation of α-ester analogues was confirmed by NOESY NMR spectroscopy. The new compounds were evaluated for their in vitro antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells. Compounds 18 showed an EC 50 value of >1.95 mg/mL. In addition, preliminary structure-activity relationship and molecular modeling of compound 18 has been studied.

Synthesis, anti-HIV activity and molecular modeling study of some new pyrimidine analogues

A new series of 2,6-diamino-5-arylazo-4-chloropyrimidine analogues (6-13) were synthesized from the pyrimidine scaffold 5, via diazotization with various amines. Nucleophilic displacement of compound 5 by ethanethiolate or arylthio nucleophiles, afforded the 4-alkylthio analogues (14-16). Treatment of compound 17 or 18 with thiourea under MWI gave the 4-thione derivatives 19 and 20, respectively. On treatment of compound 20 with 2-mercaptoacetic acid furnished the 4-thio analogue (21). Reaction of compound 19 or 20 with sodium hypochlorite followed by ammonium hydroxide afforded the 4-aminothio analogues 22 and 23, respectively. Oxidation of compound 23 with H 2 O 2 led to the 4-sulphonamide derivative 24. All new compounds were evaluated for their in vitro antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells. Compounds 14-16 and 21 showed an EC 50 values of > 2.12, 1.99, 1.80 and 1.92 μg/mL, respectively. In addition, preliminary structure-activity relationship and molecular modeling of compound 15 has been studied.

New triazolothiadiazole and triazolothiadiazine derivatives as kinesin Eg5 and HIV inhibitors: synthesis, QSAR and modeling studies

Abstract A new series of fused 1,2,4-triazoles, namely 6-aryl-3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 3a–h and 4a–f as well as 6-aryl-3-(furan-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 5a–h, were synthesized by the condensation of 4-amino-5-(furan-2-yl)-4H-1,2,4-triazole-3-thiol (2) with substituted aromatic acids and phenacyl bromides, respectively. The structures of the newly synthesized compounds were established using spectroscopic analysis, while that of 3e was confirmed independently by a single-crystal X-ray structure determination. The compounds were evaluated for their antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells using an MTT assay. In a docking study, 4b interacted with several amino acids in the reverse transcriptase (RT) binding site of HIV-1. Some new analogues were selected for evaluation of their Eg5 inhibitory activity using an in vitro malachite green ATPase assay. The QSAR of these new analogues was studied as well.

Synthesis, Antiviral and Kinesin Eg5 Activities of New Indomethacin Analogues

Aim: Synthesis, characterization, anti-HIV, anti-HCV and kinesin activities of new indomethacin analogues have been carried out. Methodology: Arylated derivatives of indomethacin via the Suzuki-Miyaura crosscoupling reaction using palladium acetate/triphenylphophineor palladium based Nheterocyclic carbene (Pd-NHC) complexe as catalysts were synthesized and characterized by the H and C and 2D NMR study. Analogously, indomethacin analogues bearing thioureido and amide moieties of various L-amino acid esters were prepared via Kabbani and coupling reactions, respectively. Results: All the new analogues were evaluated In vitro for their antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells using MTT assay. Compounds 28, 31 and 32 were evaluated In vitro for their inhibitory activity against hepatitis virus C (HCV) in the Huh 5-2 replicon system (type 1b, Con1 strain). Additionally, some analogues were screened for their inhibitory activity against the ATPase enzyme and the motor-protein Kinesin Eg5.In conclusion, Compounds 31 and 39 showed anti-HIV activity with IC50 values of >1.81 and > 3.21μM (CC50 of 3.31 and 28.89μM), resulting in selectivity indexs (SI) of 6 and 9, respectively. Conclusion: Compounds 31 and 39 displayed better anti-HIV activity than the other derivatives (SI = 6 and 9, respectively). Compound 27 showed ATPase inhibition value of 48% at 100 μM concentration. Original Research Article American Chemical Science Journal, 4(4): 516-536, 2014 517

Discovery of Piperidine‐Linked Pyridine Analogues as Potent Non‐nucleoside HIV‐1 Reverse Transcriptase Inhibitors

In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild-type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10 nM, CC50 ≥146 μM, SI≥14 126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2.2 nM, CC50 =28 μM, SI=12 884) against wild-type HIV-1. Compound BD-e2 (EC50 =5.1 nM) shows greater antiviral efficacy against wild-type HIV-1 than do the four reference drugs nevirapine, delavirdine, efavirenz, and zidovudine. Many compounds were also found to be active against the frequently observed drug-resistant double mutant (K103N+Y181C) HIV-1 strain. Herein we report the design, synthesis, anti-HIV evaluation, preliminary structure-activity relationships, and molecular simulations of novel piperidine-linked pyridine analogues.

Synthesis and anti-HIV Activity of New Fused Chromene Derivatives Derived from 2-Amino-4-(1-naphthyl)-5-oxo-4H,5H-pyrano[3,2- c]chromene-3-carbonitrile

A new series of pyrano-chromene and pyrimido pyrano-chromene derivatives were synthesized starting from 2-amino-4-(1-naphthyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (6). The structures of the synthesized compounds were elucidated by spectral data. Compounds 6-11, 13-15 and 18 have been selected for an inhibitory activity screening against HIV-1 and HIV-2 in MT-4 cells.

Synthesis, Crystal Structure and Anti-HIV Activity of 2- Adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles

Two series of 2-adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles (4a-l and 5a-l) were synthesized by cyclodehydration of adamantan-1-carboxylic acid/adamantylacetic acid with various aryl hydrazides (3a-l) in the presence of POCl(3). The synthesis was supported by spectroanalytical techniques and verified further by crystal structure determination of compounds 4e and 5k. The synthesized compounds were screened for their inhibitory activity against HIV-1 and HIV-2 in MT-4 cells. Compound 5b exhibited a moderate activity in vitro for the replication of both virus types, suggesting for further structural modification as a new lead in the development of an antiviral agent.

New Aryl-1,3-thiazole-4-carbohydrazides, Their 1,3,4-Oxadiazole-2- thione, 1,2,4-Triazole, Isatin-3-ylidene and Carboxamide Derivatives. Synthesis and Anti-HIV Activity

A series of isatin-3-ylidene (6a-i) and arylthiazolyl-1,3,4-oxadiazole-2-thione derivatives 7a-i derived from arylthiazolyl carbohydrazide analogs 4a-i were synthesized. Analogously, coupling of 4f with various amino acid methyl esters in the presence of HOBt/DCC reagents afforded the carboxamide derivatives 9a-d. The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. All compounds are inactive, except compounds 9b and 9c which showed inhibition of HIV-1 with EC50 = 2:34 μg mL-1, and 1.12 μg mL-1 with therapeutic indexes (SI) of 9 and &lt;1, respectively.